Decades ago, postmenopausal hormone replacement (HT) was considered the panacea for midlife women. Prevention of the age-related cognitive decline was among the top alleged benefits of this therapy. However, the data from the WHI-WHIMS study showed the opposite, indicating worsening of several cognitive domains in hormone users [1,2]. Since WHIMS recruited women who were 65 years or older, it became crucial to investigate the effects of HT in the early menopause as well. Alzheimer's disease (AD) is more prevalent in women, who have two-fold greater lifetime risk of developing AD compared to men [3]. This sex difference in incidence raises questions on the potential contribution of menopause-related hormonal deficiencies, and addresses issues specific to women.

Estrogen has been implicated in the pathophysiology of AD. This potential association is very complex, since there are differences between the scenarios of natural menopause versus surgical menopause, and between younger and older women [4]. Although loss of intrinsic estrogen has been associated with cognitive decline, natural menopausal transition probably does not have important effects on episodic memory or most other cognitive skills. However, as presented in a recent study which evaluated the change in cognition over approximately 2.7 years in healthy women undergoing bilateral ovary removal, surgical menopause was associated with performance declines in visual memory for those who had an oophorectomy after 45 years of age and in semantic memory for those who had oophorectomy before 45 years of age compared with natural menopause [5]. The Early versus Late Intervention Trial with Estradiol (ELITE) investigated risk parameters for cognitive decline in healthy postmenopausal women [6]. ELITE was a double-blinded, placebo-controlled clinical trial randomizing 643 postmenopausal women. In order to test the 'timing hypothesis', women were recruited into two cohorts: early menopause (n = 271), defined as within 6 years of menopause, and late menopause (n = 372), defined as 10 or more years post-menopause. A comprehensive battery of neuropsychological tests and metabolic parameters was administered before randomization, at about 2.5 years, and at each participant's final study visit, approximately 5 years after randomization. Women were randomized to receive either HT (17β-estradiol, 1 mg daily) or placebo. Women who had not undergone a hysterectomy also used vaginal 4% progesterone (or placebo) gel for the last 10 days of each month. Study data showed that, compared with healthy women, women with poor metabolism had significantly lower executive, global and memory cognitive performance. A general improvement in cognitive performance was observed in women randomized to HT.

In the laboratory, estrogen reduces β-amyloid formation, diminishes hyperphosphorylation of tau protein, and increases apolipoprotein expression. This effect in women was repeatedly investigated. A sophisticated approach was employed in the Kronos Early Estrogen Prevention Study (KEEPS), a randomized, double-blinded, placebo-controlled clinical study recruiting participants within 5–36 months past menopause [7]. One of the study arms included women who received 50 μg/day transdermal 17β-estradiol for 4 years. Oral progesterone (200 mg/day) was given to active treatment groups for 12 days each month. Pittsburgh compound B (PiB) PET imaging was performed approximately 7 years post randomization and 3 years after stopping randomized treatment. Those assigned to transdermal 17β-estradiol (n = 21) had lower PiB standard unit value ratio compared to those receiving placebo (n = 30) after adjusting for age (odds ratio 0.3; 95% confidence interval 0.11–0.83). This effect was even more pronounced in the apoE ɛ4 carriers, transdermal 17β-estradiol-treated women (n = 10). This small subgroup had a much lower PiB standard unit value ratio compared to those women given placebo (n = 5) (odds ratio= 0.04; 95% confidence interval 0.004–0.44). The study concluded that transdermal 17β-estradiol was associated with a reduced amyloid-β deposition, particularly in apoE ɛ4 carriers. Still, the data from the 4 years of the clinical trial only (mean follow-up 2.8 years) could not point at apparent treatment-related benefits in cognitive outcomes [8].

As mentioned above, a discrepancy in the findings between the earlier observational studies and the WH-WHIMS cohorts raised once again the probable importance of age and age at start of HT as major determinants of the consequences of treatment. WHIMS was a study in women 65–79 years old, and thus might younger women react differently? The WHI investigators were aware of this question, and therefore analyzed data retrieved from the youngest participants, women aged 50–55 [9]. This WHIMS-Young cohort was indeed different from the older cohort, as it concluded that global cognitive function scores, as well as any individual cognitive domain in women who had been assigned to HT were similar to those from women assigned to placebo. The review of Maki discusses the relevance of the 'window of opportunity' concept in regard to cognition [10]. Data are not strong enough to allow concrete conclusions, yet it seems that HT has some favorable cognitive effects in young postmenopausal women with vasomotor symptoms. Whether or not hormone therapy has an effect on already demented women remains to be further explored as well.